PROJECT SUMMARY/ABSTRACT The goal of this NIDDK Mentored Research Scientist Career Development (K01) Award is to provide funding for the principal investigator (PI), Dr. Manoj Thapa, developing into an independent biomedical research scientist in the field of liver disease and liver immunology. After joining the Dr. Arash Grakoui?s laboratory at Yerkes National Primate Research Center of Emory University, the PI initiated a new project with the intention of identifying factors that lead to T and B cell differentiation during liver disease. In this K01 proposal, PI will build upon his previous expertise and study the dynamics of cellular immune responses focusing on the mechanisms of B cell dysregulations during chronic liver diseases associated with chronic hepatitis C virus (HCV) infection, alcohol liver disease (ALD) and nonalcoholic steatohepatitis (NASH). PI will be allocating 75% of his time for the research as proposed in this K01 application and 25% of the time to didactic trainings such as participation in seminars, lab meetings, manuscript preparation, grant writing, and national and international conferences. This project will focus on the contribution of MyD88-specific toll like receptor (TLR) activation and BAFF/BLyS signaling in the B cell-mediated pathogenesis of liver disease and autoimmune disorder. The incidence of end- stage liver disease (ESLD) is increasing in the United States and poses a serious economic and clinical burden as it is expected to afflict more than 300 million individuals worldwide. Chronic HCV infection, ALD, and NASH account for the majority of ESLD cases, with chronic HCV associated with the highest incidence of liver transplantation. The orthotopic liver transplantation is the optimal treatment for ESLD and carries a high cost while benefitting relatively few. Understanding the mechanisms of the cellular immune responses that contributes to fibrosis and the progression of ESLD is critical for effective therapeutic intervention. PI will approach these questions from two different directions. First, by using murine models of experimental liver fibrosis, PI will delineate the role of MyD88-specific TLR signaling and BAFF/BLyS signaling in B cell dysfunction, liver fibrosis and autoimmune disorder associated with liver disease. Then, he will build his career into human translational science to improve an understanding of cellular immune response in human chronic liver diseases including HCV, ALD and NASH patients. These diseases while different have common themes (i.e. fibrosis/cirrhosis) and therefore proposed in this study to compare and contrast the effect of a viral infection (HCV), an inflammation without infection (NASH) and the absence of virus and an on-going inflammatory insult at the time of transplant (ALD) (alcohol abstinence is required for a minimum of 6 months prior to transplant at Emory Transplant Center) on B cell activation and function. The application will provide an immunological basis for the study of targeting therapeutics to reverse the progression and clinical sequelae of liver fibrosis. During the K01 award, PI plans to further master skills and acquire proficiency in the area of human liver biology, chronic liver disease and liver immunology by participating in didactic courses offered by the Emory University and other recognized professional organizations, training in responsible conduct of research, enrolling in Certificate Program in Translational Research, Junior Faculty Development Course and Faculty Development Lecture Series. PI plans to acquire in-depth trainings in human specimens (liver explants and blood) processing and immunological analysis of human tissues in understanding of the complex interaction between the immune system and the liver in multifactorial disease including liver fibrosis, cirrhosis, ESLD, and autoimmune disorders. In addition, PI also plans to actively participate in weekly or monthly seminar series available at Emory University and attend annual national conferences on Fibrosis, Signaling pathways, Immunology, Liver Diseases, and Hepatitis C Virus (HCV). Furthermore, PI will take advantage of multiple grant-writing workshops available at Emory University and plan to apply for NIH grants via the R21 mechanism in the third year, and R01 in the fourth year submitting revisions as needed during the fourth and fifth years. PI will greatly benefit from a team of mentors including Dr. Arash Grakoui, an expert in HCV infection and liver immunology, Dr. Max Cooper, a foremost B cell immunologist, Dr. Frank Anania, an expert clinician in hepatology and gastroenterology, and Dr. Bali Pulendran, an established immunologist. This group of eminent scientists will provide additional expertise and training needed for the PI to achieve his short-term goal of achieving the scientific independence as well as the long-term goal of becoming an established biomedical research scientist and develop a research program to determine the fundamental questions regarding chronic liver disease and associated autoimmune disorders.